The basic helix-loop-helix transcription factor TCF4 (aka E2-2) has been implicated broadly in human CNS function. TCF4 was confirmed in several large GWAS studies as one of the rare highly replicated schizophrenia susceptibility genes, and when haplo-insufficient TCF4 is the causative factor for Pitt-Hopkins Syndrome (PTHS). PTHS has compelling attributes in terms of human cognitive function, being associated with pronounced memory deficits, autistic behaviors, and importantly an almost complete lack of language development. Thus, understanding the roles and function of TCF4 in the CNS is highly significant with respect to human language and auditory cognition, memory function, autism spectrum behavior, and schizophrenia susceptibility. Despite the clear importance of TCF4 function in the human CNS, the basic neurobiology of TCF4 has been only sparsely studied. Thus, this Project will use genetically engineered mouse models to assess the role of TCF4 in memory, social interactions and communication, hippocampal synaptic plasticity, synaptic anatomy, and epigenomic and transcriptional regulation in the CNS. The central hypothesis of the proposed studies is that TCF4 regulates the brain's ability to trigger long-term synaptic plasticity and memory formation by actively regulating transcriptional activity in response to behavioral experience. The approach will be to use both germline constitutive knockout and acute knockdown or deletion of TCF4 in the adult mouse hippocampus, coupled with extensive behavioral, electrophysiological, and transcriptomic/epigenomic characterization, to determine if TCF4 function is necessary in an ongoing fashion for normal memory and synaptic plasticity in the mature CNS. The studies will capitalize not only upon the available germline knockout line but also upon an already-available floxed TCF4 allele mouse line, and combine these mice with both virus- driven cre expression in the adult hippocampus and post-developmental CaMKII promoter-driven forebrain neuron-selective cre expression to achieve inducible post-developmental attenuation of CNS TCF4 function in vivo. Using these novel mouse models we will undertake three Specific Aims. Aim 1 will test the hypothesis that TCF4-deficient mice exhibit cognitive memory and social interaction deficits, and also test the hypothesis that TCF4-deficient mice exhibit altered synaptic plasticity. Aim 2 will comprise a significant translational component of the studies and will test the hypothesis that transcription-promoting Histone DeAcetylase Inhibitors (HDACi) will restore learning, memory, and synaptic plasticity in TCF4-deficient mice, as proof-of- concept that behavioral deficits and plasticity deficits in PTHS model mice can be reversed pharmacologically with HDACi. Aim 3 will test the hypothesis that loss of TCF4 function triggers secondary alterations in chromatin structure, DNA methylation, and gene transcription in the mature CNS. Toward this end, we will use the unbiased approach of utilizing MBD-seq, mRNA-seq, and small RNA-seq approaches for a comprehensive analysis of potential transcriptomic and epigenomic alterations in TCF4-deficient mice.